VA Class:CN101

AHFS Class:

• Opioid Agonists 28:08.08

Generic Name(s):

• Meperidine Hydrochloride

Associated Monographs

• Opiate Agonists General Statement

Meperidine hydrochloride is a synthetic phenylpiperidine-derivative opiate agonist.

Meperidine is a strong analgesic used in the relief of moderate to severe pain. The drug has been used to relieve the pain of myocardial infarction, although it is probably not as effective as morphine sulfate. Meperidine also is used parenterally for preoperative sedation, as a supplement to anesthesia, and to provide analgesia during labor. Meperidine is used in patients with acute pulmonary edema for its cardiovascular effects and to allay anxiety. The drug should not be used in the treatment of pulmonary edema resulting from a chemical respiratory irritant.

Use of meperidine hydrochloride as first-line opiate therapy is discouraged because of the central excitatory toxicity of its metabolite, normeperidine.245,247 Use of meperidine hydrochloride for management of chronic pain is discouraged because of its short duration of effect and the risk of normeperidine accumulation and resultant central excitatory toxicity with repeated or large doses.248 Some experts also discourage use in children.245

For further information on the role of opiate analgesics in the management of pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Meperidine hydrochloride is administered orally; by subcutaneous, IM, or slow IV injection; or by slow, continuous IV infusion. The drug is least effective when given orally.

Some experts discourage administration of meperidine hydrochloride by the oral route because of extensive first-pass metabolism in the liver and resultant increased formation of the toxic metabolite, normeperidine.245

Each dose of the meperidine hydrochloride oral solution should be taken in one-half glassful of water, since the undiluted solution may produce slight topical anesthesia on mucous membranes.

IM administration of opiate analgesics is discouraged, since IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent analgesia.246,247,248,430 However, when repeat doses are necessary and IV therapy is not used, the IM route is preferred over subcutaneous administration because of occurrence of local tissue irritation and induration following subcutaneous injection.

When meperidine hydrochloride is administered IM, it should be injected into a large muscle mass, taking care to avoid nerve trunks.

If IV administration is required, meperidine dosage should be decreased and the commercially available injections should be administered very slowly, preferably as dilute solutions. Alternatively, the commercially available injection containing 10 mg/mL, which should be used only with a compatible infusion device and does not require further dilution, may be used; the 10-mg/mL injection is intended for single use only, and unused portions should be appropriately discarded. When meperidine is given parenterally, especially by the IV route, the patient should be lying down. An opiate antagonist and facilities for administration of oxygen and control of respiration should be available during and immediately following IV administration of the drug.

Preservative-free injections of meperidine hydrochloride have been injected or infused epidurally†; specialized techniques are required for administration of the drug by this route, and such administration should be performed only by qualified individuals familiar with the techniques of administration, dosages, and special patient management problems associated with epidural meperidine hydrochloride administration.

As with other parenteral products, meperidine hydrochloride injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Meperidine hydrochloride should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435

Meperidine hydrochloride generally should be limited to short-term use (a few days) because of the risk of accumulation of the toxic normeperidine metabolite with repeated or large doses.245,247,248

Reduced meperidine hydrochloride dosage is indicated in poor-risk patients and in very young or geriatric patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 In patients receiving phenothiazines or other tranquilizers concomitantly with meperidine, the dose of meperidine should be reduced by 25-50% since these drugs potentiate the adverse effects of meperidine.

The usual adult oral, IM, or subcutaneous dosage of meperidine hydrochloride is 50-150 mg every 3-4 hours as necessary. When the drug is administered by slow, continuous IV infusion, the usual adult dosage is 15-35 mg/hour. Patients receiving meperidine hydrochloride for longer than 48 hours or in total dosages exceeding 600 mg over 24 hours are at increased risk of toxicity from the normeperidine metabolite.245 (See Pharmacokinetics: Elimination.)

Children may receive 1.1-1.8 mg/kg orally, IM, or subcutaneously every 3-4 hours as necessary. Alternatively, children may receive 175 mg/m² daily in 6 divided doses administered by the oral, IM, or subcutaneous route. Single pediatric doses should not exceed 100 mg.

The usual adult preoperative dose of meperidine hydrochloride is 50-100 mg IM or subcutaneously 30-90 minutes before the beginning of anesthesia. Children may receive 1-2.2 mg/kg (maximum up to the adult dose) IM or subcutaneously 30-90 minutes before the beginning of anesthesia. As a supplement to anesthesia, meperidine may be given by repeated slow IV injections of a dilute solution (e.g., containing 10 mg/mL) or by continuous IV infusion of a more dilute solution (e.g., containing 1 mg/mL).

To provide analgesia during labor, 50-100 mg of meperidine hydrochloride may be administered IM or subcutaneously when labor pains become regular. If necessary, this dose may be repeated at 1- to 3-hour intervals.

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Dosage in Renal and Hepatic Impairment

Adjustment in the dose, frequency, and/or duration of meperidine therapy may be necessary in patients with hepatic impairment since accumulation of the drug and/or its active metabolite, normeperidine, can occur.200,204,205,206,207,208,209,210,211,212,213 In addition, oral bioavailability of meperidine may be increased substantially in patients with hepatic impairment.212,213 (See Pharmacokinetics.) Certain adverse effects secondary to CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) have been attributed to accumulation of normeperidine.200,201,204,205,206,209,210,211,240

Because of the potential for accumulation of normeperidine in patients with renal impairment, use of meperidine, particularly high or repeated doses, generally should be avoided in these patients.245,246,247 If meperidine is used, adjustment of the dose, frequency, and/or duration of therapy is likely to be necessary.200,204,205,206,207,208,209,210,211,212,213 In patients with end-stage renal failure, meperidine should be avoided because of the risk of accumulation of this metabolite.200,205,207,208,211,220

Meperidine shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.)

Since meperidine may increase ventricular response rate through a vagolytic action, the drug should be used with caution in patients with atrial flutter and other supraventricular tachycardias. In one study in patients with myocardial infarction, meperidine hydrochloride in IV doses of 100 mg appeared to cause various circulatory disturbances including increases in mean aortic pressure, systemic vascular resistance, and heart rate. Occasional occurrence of sinus tachycardia in postoperative patients has been attributed to meperidine.

Serotonin syndrome has been reported during concomitant use of opiate agonists, including meperidine, and serotonergic drugs at recommended dosages.255,400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

Inadvertent IM injection of meperidine into or near nerve trunks can result in sensory-motor paralysis, which may or may not be transient.

Some commercially available formulations of meperidine hydrochloride contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Meperidine should be used with caution in patients at risk for accumulation of normeperidine (e.g., those with renal or hepatic impairment) and during prolonged therapy and/or therapy with high dosages in other patients (e.g., those with sickle cell anemia or CNS disease, burn patients, cancer patients) at risk for neurotoxic effects of the metabolite.200,204,205,206,207,208,209,210,211,212,213,220,240,245 Such patients should be observed closely for potential manifestations of CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) associated with accumulation of the metabolite.200,204,205,206,208,209,210,211,220,240

Geriatric Precautions

Elimination of meperidine is slower in geriatric patients than in younger patients.244 In addition, geriatric patients, especially those with decreased renal and hepatic function, may be at greater risk for adverse CNS effects secondary to accumulation of the toxic metabolite normeperidine.242,243,244 Therefore, meperidine should be used with caution in geriatric patients, taking into account the potential risks and benefits to the patient, and dosage adjustment should be considered.242,243,244

Monoamine Oxidase Inhibitors

Since virtually all the reported incidents of opiate agonist interaction with monoamine oxidase (MAO) inhibitors have occurred in patients receiving meperidine, meperidine is contraindicated in patients who are receiving these drugs or have received these drugs during the previous 14 days. In some patients receiving MAO inhibitors, therapeutic doses of meperidine have produced coma, severe respiratory depression, cyanosis, and hypotension resembling the typical syndrome of acute opiate agonist overdosage. Although the mechanism for this interaction has not been elucidated, it has been suggested that these adverse effects may be associated with preexisting hyperphenylalaninemia. In other patients on MAO inhibitor therapy, meperidine has caused hyperexcitability, seizures, tachycardia, pyrexia, and hypertension. IV hydrocortisone or prednisolone has been used to treat severe reactions, with the addition of IV chlorpromazine hydrochloride in patients exhibiting hypertension and hyperpyrexia. The usefulness and safety of opiate antagonists in the treatment of these reactions are unknown. (See also Drug Interactions: Drugs Associated with Serotonin Syndrome.)

Drugs Associated with Serotonin Syndrome

Serotonin syndrome has occurred in patients receiving opiate agonists, including meperidine, in conjunction with other serotonergic drugs,249,250,251,252,254,255,400 including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and MAO inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

Meperidine should not be used concomitantly with other serotonergic agents; use of meperidine in patients who are receiving or have recently (within 14 days) received an MAO inhibitor is contraindicated.255 (See Drug Interactions: Monoamine Oxidase Inhibitors.) If serotonin syndrome is suspected, treatment with meperidine, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Isoniazid

Administration of meperidine to patients on isoniazid therapy has been reported to aggravate the adverse effects of isoniazid.

Estrogens and Progestins

Limited data indicate that oral contraceptives or estrogens may inhibit meperidine metabolism; the clinical importance of this inhibition on analgesic effectiveness of meperidine has not been determined.

For further information about drug interactions involving opiate agonists (including meperidine hydrochloride), see Drug Interactions in the Opiate Agonists General Statement 28:08.08.

Pharmacology

Although the duration of respiratory depression produced by meperidine may be shorter than that of morphine, equianalgesic doses of meperidine hydrochloride and morphine sulfate produce the same degree of respiratory depression. The sedative and euphoric effects of equianalgesic doses of meperidine may be greater than those of morphine but reports are conflicting. Meperidine causes little or no constipation and has antitussive activity only in analgesic doses. Systemic administration of meperidine may cause corneal anesthesia which can abolish the corneal reflex. Topical application of the drug produces considerable local anesthesia, but meperidine is not utilized for local anesthesia because it also produces local irritation.

Pharmacokinetics

Absorption

Following oral administration, meperidine undergoes extensive metabolism on first pass through the liver, with approximately 50-60% of a dose reaching systemic circulation unchanged.207,212,213,214 In patients with hepatic impairment (e.g., liver cirrhosis), oral bioavailability of meperidine increases to approximately 80-90%.212,213 Meperidine is less than one-half as effective when given orally as when given parenterally. Approximately 80-85% of an IM dose of the drug reportedly was absorbed within 6 hours after intragluteal injection in healthy adults in one study;217 however, absorption from the IM injection site appears to show considerable interindividual variation and may depend on the site of injection, dose, and patient-specific variables.212

Meperidine appears to have a more rapid onset and shorter duration of action than does morphine. Following oral administration of meperidine, peak analgesia occurs within one hour and gradually declines over 2-4 hours. Peak analgesia occurs about 40-60 minutes after subcutaneous administration and 30-50 minutes after IM administration. Analgesia may be maintained for 2-4 hours following subcutaneous or IM administration.

Distribution

Meperidine is approximately 60-80% bound to plasma proteins,212 principally albumin and α₁-acid glycoprotein (α₁-AGP).212 There is some evidence that the ratio of bound to free drug is correlated with plasma α₁-AGP concentrations.212 In patients with cirrhosis or active viral hepatitis, the extent of protein binding does not appear to be affected.215,216

Meperidine crosses the placenta207,218 and is distributed into milk.

Elimination

Plasma meperidine concentrations decline in a biphasic manner,207,219 with a half-life in the initial distribution phase (t_½α) of 2-11 minutes207,215,219 and a half-life in the terminal elimination phase (t_½β) of 3-5 hours200,204,205,207,213,214,215,216,217,219 in individuals with normal renal and hepatic function. The elimination half-life is prolonged in patients with hepatic dysfunction,207 averaging about 7-11 hours in patients with liver cirrhosis207,213,215 or active viral hepatitis.207,216

Meperidine is metabolized principally in the liver. The drug is biotransformed mainly by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine may also undergo N -demethylation to normeperidine followed by hydrolysis and partial conjugation. Other metabolites also have been identified, but only normeperidine has been detected in blood or plasma.212 When urine pH is uncontrolled, approximately 5-30% of a dose of meperidine is excreted in urine as the N -demethylated derivative and about 5% is excreted unchanged; however, the relative proportion of the drug excreted in urine unchanged and as metabolites is pH dependent. Meperidine and normeperidine are found in acid urine whereas meperidinic and normeperidinic acids in the free and conjugated form are present in alkaline urine. Excretion of the unchanged drug and normeperidine is enhanced by acidifying the urine.

Normeperidine is pharmacologically active, reportedly exhibiting about half the analgesic potency of meperidine but twice the CNS stimulant (e.g., seizure-inducing) potency.200,201,202,203,204,205,206,207,208,209,210,211 Various toxic effects secondary to CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) have been attributed to accumulation of this metabolite.200,201,204,205,206,209,210,211,240 The elimination half-life of normeperidine is substantially longer than that of meperidine, reportedly ranging from 8-21 hours,200,204,205,207,208,210 and may be prolonged (e.g., to longer than 30 hours) in patients with renal impairment.200,204,205,207,208,210,211 Accumulation of this metabolite may occur with repeated, high doses of the drug and in patients with renal or hepatic impairment.200,204,205,206,207,212,213,240

Chemistry and Stability

Chemistry

Meperidine hydrochloride is a synthetic phenylpiperidine-derivative opiate agonist. Meperidine hydrochloride occurs as a fine, white, crystalline powder with a slightly bitter taste and is very soluble in water and soluble in alcohol. Meperidine hydrochloride injection has a pH of 3.5-6.

Stability

Meperidine hydrochloride preparations should be protected from light and stored at a temperature less than 40°C; meperidine hydrochloride tablets should be stored at 15-30°C and meperidine hydrochloride injections should be stored at 15-25°C. Freezing of meperidine hydrochloride oral solutions or injections should be avoided. Meperidine hydrochloride oral solutions or tablets should be stored in tight or well-closed containers, respectively.

Meperidine hydrochloride injection has been reported to be physically or chemically incompatible with solutions containing aminophylline, barbiturates, ephedrine sulfate, heparin sodium, hydrocortisone sodium succinate (in a ratio of 2 parts of hydrocortisone sodium succinate to 1 part of meperidine hydrochloride), methicillin sodium (no longer commercially available in the US), methylprednisolone sodium succinate, morphine sulfate, nitrofurantoin sodium, oxytetracycline hydrochloride, sodium bicarbonate, sodium iodide, tetracycline hydrochloride, thiamylal sodium, and thiopental sodium (no longer commercially available in the US). Meperidine hydrochloride also has been reported to be incompatible with solutions containing potassium iodide, aminosalicyclic acid, and salicylamide. Specialized references should be consulted for specific compatibility information.

Additional Information

For further information on the chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, and dosage and administration of meperidine hydrochloride, see the Opiate Agonists General Statement 28:08.08.

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